We have continued to extend our studies of cortical processing in patients with schizophrenia and their healthy siblings in an effort to further refine the phenomenology of this increased risk trait related to cortical function. These studies have involved 1) a more refined analysis of subprocesses involved in memory and cognitive control, 2) novel approaches to fMRI signal analysis, and 3) the continued acquisition of brain processing data. We use genes associated with risk for schizophrenia to learn about molecular and neural system mechanisms related to key biologic aspects of the illness. Using convergent data from cognitive, imaging and basic science methods, we hope to identify new approaches to treatment based on validated neural mechanisms. Validation of genetic association with schizophrenia provides biologic evidence of the effect of schizophrenia-associated risk alleles on relevant measures of brain development and function assayed with cognitive and neuroimaging approaches in healthy and ill subjects. Our rationale is that the discovery of susceptibility genes for psychiatric disorders, which represent the first objective clues to the etiologies of these conditions, will lead to identifying pathogenic mechanisms and new therapies. However, the statistical evidence of clinical association is an uncertain starting point, as statistical evidence cannot prove causation. We are not focused on discovering risk-associated genes, but on generating biologic hypothesis and testing based on genes of informed interest. Genetic association must be translated into biologic mechanisms involving molecular networks/pathways and neural systems for the discovery of new therapeutic targets. Our investigators have demonstrated that multiple genes implicated in schizophrenia converge on patterns of cognition and related brain processing that have been identified as intermediate phenotypes related to genetic risk for schizophrenia. These findings help translate causative mechanisms at the cellular levels (i.e. genes) into pathophysiologic mechanisms at the level of neural systems involved in the clinical state (i.e. abnormal cortical information processing). These results indicate that there are likely many molecular pathways to the biological and clinical features of the disorder. The investigative impact of these findings is illustrated in the rapidly growing worldwide research interest in mapping effects of psychiatric risk-associated genes onto aspects of brain structure and function related to the biology of these disorders. Genetic associations confirmed and elucidated by studies in CBDB also form the basis for collaborations with basic researchers in the Genes, Cognition and Psychosis Program (GCAP) to develop cellular and transgenic animal models based on high-risk alleles and haplotypes of susceptibility genes or on altered gene processing or expression patterns in tissue related to risk-associated alleles. The goal of these studies is to elucidate risk-associated mechanisms at multiple levels of biology, from gene function, to cell biology, to neural systems function. This systems biology approach of hierarchical and convergent hypothesis testing of biological association has led to the identification of at least five novel potential therapeutic targets that are being pursued as a major emphasis of our future work towards therapeutic trials.